A Novel Glucokinase Activator Modulates Pancreatic Islet and Hepatocyte Function

Efanov, Alexander M.; Barrett, David; Brenner, Martin; Briggs, Stephen L.; Delaunois, Annie; Durbin, Jim D.; Giese, U.; Guo, Haihong; Radloff, Mark; Gil, Gema Sanz; Sewing, Sabine; Wang, Yong; Weichert, Andreas; Zaliani, Andrea; Gromada, Jesper

doi:10.1210/en.2005-0377

Cited by 131 publications

(144 citation statements)

References 29 publications

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“…Previous studies had revealed that induction of IRS2 results in improved glucose sensing and b-cell proliferation through enhancing insulin/IGF-1 signaling in islets [8,15]. Expression of PDX-1 and glucokinase was associated with glucose sensing and b-cell proliferation, respectively [7,11,12]. Thus, levels of PDX-1 and glucokinase mRNA were also measured in islets treated with herb extracts (Fig.…”

Section: Glucose-stimulated Insulin Secretion In Isletsmentioning

confidence: 85%

Extracts of Rehmanniae radix, Ginseng radix and Scutellariae radix improve glucose-stimulated insulin secretion and β-cell proliferation through IRS2 induction

et al. 2007

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Recent studies have revealed that b-cell dysfunction is an important factor in developing type 2 diabetes. b-cell dysfunction is related to impairment of the insulin/ IGF-1 signaling cascade through insulin receptor substrate-2 (IRS2). The induction of IRS2 in b-cells plays an important role in potentiating b-cell function and mass. In this study, we investigated whether herbs used for treating diabetes in Chinese medicine-Galla rhois, Rehmanniae radix, Machilus bark, Ginseng radix, Polygonatum radix, and Scutellariae radix-improved IRS2 induction in rat islets, glucose-stimulated insulin secretion and b-cell survival. R. radix, Ginseng radix and S. radix significantly enhanced glucose-stimulated insulin secretion compared to the control, i.e., by 49, 67 and 58%, respectively. These herbs induced the expression of IRS2, pancreas duodenum homeobox-1 (PDX-1), and glucokinase. The increased level of glucokinase could explain the enhancement of glucosestimulated insulin secretion with these extracts. Increased PDX-1 expression was associated with b-cell proliferation, which was consistent with the cell viability assay. In conclusion, R. radix, Ginseng radix and S. radix had an insulinotropic action similar to that of exendin-4.

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Section: Glucose-stimulated Insulin Secretion In Isletsmentioning

confidence: 85%

Extracts of Rehmanniae radix, Ginseng radix and Scutellariae radix improve glucose-stimulated insulin secretion and β-cell proliferation through IRS2 induction

et al. 2007

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“…GK plays an important role as a glucose sensor for controlling plasma glucose homeostasis by enhancing insulin secretion from pancreatic ␤-cells and glucose metabolism in the liver (1,2), which provides rational expectations that enhancement of GK activity would be a novel therapeutic strategy for type 2 diabetes. Consistent with this rationale, recently discovered small molecule allosteric activators of GK have been demonstrated to have antidiabetic efficacy in rodents (3,4).…”

mentioning

confidence: 85%

An Allosteric Activator of Glucokinase Impairs the Interaction of Glucokinase and Glucokinase Regulatory Protein and Regulates Glucose Metabolism

Futamura

Hosaka

Kadotani

et al. 2006

Journal of Biological Chemistry

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Glucokinase (GK) plays a key role in the control of blood glucose homeostasis. We identified a small molecule GK activator, compound A, that increased the glucose affinity and maximal velocity (V max ) of GK. Compound A augmented insulin secretion from isolated rat islets and enhanced glucose utilization in primary cultured rat hepatocytes. In rat oral glucose tolerance tests, orally administrated compound A lowered plasma glucose elevation with a concomitant increase in plasma insulin and hepatic glycogen. In liver, GK activity is acutely controlled by its association to the glucokinase regulatory protein (GKRP). In order to decipher the molecular aspects of how GK activator affects the shuttling of GK between nucleus and cytoplasm, the effect of compound A on GK-GKRP interaction was further investigated. Compound A increased the level of cytoplasmic GK in both isolated rat primary hepatocytes and the liver tissues from rats. Experiments in a cell-free system revealed that compound A interacted with glucose-bound free GK, thereby impairing the association of GK and GKRP. On the other hand, compound A did not bind to glucose-unbound GK or GKRPassociated GK. Furthermore, we found that glucose-dependent GK-GKRP interaction also required ATP. Given the combined prominent role of GK on insulin secretion and hepatic glucose metabolism where the GK-GKRP mechanism is involved, activation of GK has a new therapeutic potential in the treatment of type 2 diabetes.There are three key aspects of type 2 diabetes pathogenesis, which are the focus of current and future therapies: insulin resistance, defective insulin secretion, and increased hepatic glucose production. Glucokinase (GK) 2 is the predominant glucose phosphorylation enzyme in pancreatic ␤-cells and hepatocytes. GK plays an important role as a glucose sensor for controlling plasma glucose homeostasis by enhancing insulin secretion from pancreatic ␤-cells and glucose metabolism in the liver (1, 2), which provides rational expectations that enhancement of GK activity would be a novel therapeutic strategy for type 2 diabetes. Consistent with this rationale, recently discovered small molecule allosteric activators of GK have been demonstrated to have antidiabetic efficacy in rodents (3, 4).To investigate the mechanism of action of GK activators, the interaction between GK and glucokinase regulatory protein (GKRP) is a key aspect. It is well known that hepatic GK activity is modulated by the endogenous inhibitor, glucokinase regulatory protein (GKRP) (5-8). GK is localized in the nucleus as an inactive complex with GKRP at low glucose concentrations and is dissociated from the GK⅐GKRP complex and translocated to the cytoplasm at high glucose concentrations, which triggers glucose disposal (9). Modulators of the GK-GKRP interaction have been shown to enhance hepatic glucose disposal (7). We recently solved the co-crystal structure of hepatic GK complex with GK activator, in which GK undergoes a large conformational change between the active and inactive forms at diffe...

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“…Since the report by Grimsby et al in 2003 [5], several glucokinase activators (GKAs) have been developed, and these have been shown to lower blood glucose in several animal models of type 2 diabetes [5][6][7][8][9][10][11][12]. In a study of beta cell function, it was reported that a GKA stimulated insulin secretion in a Ca 2+ -dependent manner in rodent islets and MIN6 cells [13], and we and others have reported that GKAs promoted beta cell proliferation and increased production of IRS2 [11,14], which is critically required for beta cell growth and survival [3,[15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Control of beta cell function and proliferation in mice stimulated by small-molecule glucokinase activator under various conditions

et al. 2012

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Aims/hypothesis We investigated changes in the expression of genes involved in beta cell function and proliferation in mouse islets stimulated with glucokinase activator (GKA) in order to elucidate the mechanisms by which GKA stimulates beta cell function and proliferation. Methods Islets isolated from mice were used to investigate changes in the expression of genes related to beta cell function and proliferation stimulated by GKA. In addition, Irs2 knockout (Irs2 −/− ) mice on a high-fat diet or a high-fat diet containing GKA were used to investigate the effects of GKA on beta cell proliferation in vivo. Results In wild-type mice, Irs2 and Pdx1 expression was increased by GKA. In Irs2 −/− mice, GKA administration increased the glucose-stimulated secretion of insulin and Pdx1 expression, but not beta cell proliferation. It was particularly noteworthy that oxidative stress inhibited the upregulation of the Irs2 and Pdx1 genes induced by GKA. Moreover, whereas neither GKA alone nor exendin-4 alone upregulated the expression of Irs2 and Pdx1 in the islets of db/db mice, prior administration of exendin-4 to the mice caused GKA to increase the expression of these genes.Conclusions/interpretation GKA-stimulated IRS2 production affected beta cell proliferation but not beta cell function. Oxidative stress diminished the effects of GKA on the changes in expression of genes involved in beta cell function and proliferation. A combination of GKA and an incretin-related agent might therefore be effective in therapy.

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A Novel Glucokinase Activator Modulates Pancreatic Islet and Hepatocyte Function

Cited by 131 publications

References 29 publications

Extracts of Rehmanniae radix, Ginseng radix and Scutellariae radix improve glucose-stimulated insulin secretion and β-cell proliferation through IRS2 induction

Extracts of Rehmanniae radix, Ginseng radix and Scutellariae radix improve glucose-stimulated insulin secretion and β-cell proliferation through IRS2 induction

An Allosteric Activator of Glucokinase Impairs the Interaction of Glucokinase and Glucokinase Regulatory Protein and Regulates Glucose Metabolism

Control of beta cell function and proliferation in mice stimulated by small-molecule glucokinase activator under various conditions

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